Angiogenesis involves extremely complicated courses including expansion of existing vessels, increase in vascular permeability, degradation of perivescular stroma, activation, proliferation and migration of endothelial cells, and formation of new capillary-like lumina.
About ⅔ of diseases causing blindness are associated with pathological angiogenesis in eyes, for example, corneal angiogenesis induced by simplex herpetic stromal keratitis, choroidal angiogenesis in age-related macular degeneration, and retinal angiogenesis in diabetic retinopathy or retinopathy of premature infant. At present, laser photocoagulation, photodynamic therapy (PDT), and thermal transpupillary therapy (TTT) etc. are conventionally used for clinically treating the ocular pathological angiogenesis. However, these treatments tend to destroy local tissues, and the long-term efficacy thereof is still unsatisfactory. Therefore, in recent years, people kept trying to develop more effective methods for treating ocular pathological angiogenesis.
When developing effective inhibitors of angiogenesis, the specificity of the ocular drugs should be sufficiently considered.
Firstly, there are many anatomical and functional barriers in eyes. Systemic administration usually cannot result in a topically sufficient drug concentration in ocular tissue due to the blood-aqueous humor barrier and blood-retina barrier. Theoretically, in topical administration, such as injection in vitreous cavity, it is difficult for any macromolecule larger than 76.5 kDa to penetrate the retina and act on the retinal and choroidal angiogenesis. When administrated on ocular surface, the drugs have to successively penetrate lipophilic the corneal epithelial cells as well as the hydrophilic corneal stroma, which are the tightly connected. Thus, merely the medications that have appropriate lipophilicity, a low molecular weight or capability to bind with the transporters (e.g., amino acid transporters, oligopeptide transporters, etc.) in ocular surface tissues can reach the anterior chamber and function effectively.
Secondly, the solubility of the drugs in the hydrophilic tears, aqueous humor, and vitreous humor is positively correlated to their effects.
Thirdly, for the above major reasons, the bioavailability of ocular drugs is very low. To improve it, the administration concentration of drugs should be increased. However, compounds for treating neoplastic angiogenesis exhibit significant toxicity, so that high dose cannot be used in either systemic or topical administration. In addition, exogenous proteins with large molecular weight are also sensitive foreign substances which may cause immune damages to eye tissues such as uveal.
Fourthly, currently a series of relatively safe endogenous inhibitors of angiogenesis, such as angiostatin consisting of plasminogen Kringle domains 1-4, have been demonstrated to significantly inhibit growth of vessel blood-dependent tumor. However, due to their relative large molecular weight and complicated spatial conformation, these inhibitors have disadvantages in preparation such as complicated recombinant expression and purification processes, residual endotoxin and so on. Because of the constraints caused by the above factors, at present, only a few medicaments are used for treating ocular angiogenesis, e.g., recombinant anti-VEGF monoclonal antibody bevacizumab (Avastin), and the recombinant fragment of anti-human VEGF monoclonal antibodies ranibizumab (Lucentis), etc. However, they are expensive, repeated intravitreal administrations are necessary, and certain risks, such as vascular embolization will be caused.
Thus, for preventing and treating neovascular eye diseases, it is extremely important to seek for the small-molecule inhibitors with specific biological activity and biocompatibility, which can penetrate all kinds of barriers in ocular tissue via non-invasive or minimally invasive administration, thereby enhancing ocular bioavailability with reduced dosage, reduced side effects either locally or systemically. Therefore, there is an urgent need in developing small molecule inhibitors of angiogenesis, which are safe, effective, and compatible with eyeball tissues.